E. de Oliveira

Temporal evaluation of body composition, glucose homeostasis and lipid profile of male rats programmed by maternal protein restriction during lactation.

Neonatal protein restriction causes lower body weight and hormonal dysfunctions in 6 months-old rats. In this model, we studied the body composition, glycogen content, serum lipid, serum protein, and hormones related to glucose homeostasis in the offspring during development. At birth, lactating rats were divided into: control dams - fed a normal diet (23% protein) and protein restricted dams - fed a diet with 8% protein. After weaning, pups received normal diet. Offspring were killed at 21, 90, and 180 days-old. Protein restricted offspring showed lower visceral fat (90th day: 14%; 180th day: 19%) and lower total fat (90th day: 16%; 180th day: 14%) that explain their lower body weight. They presented lower glycemia (180th day: 17%), lower insulinemia (21st day: 63%; 180th day: 24%), higher adiponectinemia (21st day: 169%), higher liver glycogen (21st day: 104%), and higher muscle glycogen (180th day: 106%), suggesting a higher insulin sensitivity. The higher serum corticosterone (50%), higher adrenal total catecholamines content (98%) as well as in vitro catecholamine secretion (26%) of adult protein restricted offspring, suggest a programming stimulatory effect upon adrenal gland. They also presented several biochemical changes, such as lower serum total protein, albumin and globulin (21st day: 17, 21, 12%, respectively), higher LDL-c (21st day: 69%), lower triglycerides (21st day: 42%; 90th day: 39%), and lower total cholesterol (180th day: 16%). Thus, maternal protein restriction during lactation induces an energy-protein malnutrition, characterized by an impairment of the pups protein anabolism and, after weaning, the lower adiposity suggests lower lipogenesis and higher lipolytic activity, probably caused by catecholamine and glucocorticoid action.

Calcium supplementation reverts central adiposity, leptin, and insulin resistance in adult offspring programed by neonatal nicotine exposure

Obesity is a worldwide epidemic. Calcium influences energy metabolism regulation, causing body weight loss. Because maternal nicotine exposure during lactation programs for obesity, hyperleptinemia, insulin resistance (IR), and hypothyroidism, we decided to evaluate the possible effect of dietary calcium supplementation on these endocrine dysfunctions in this experimental model. Osmotic minipumps containing nicotine solution (N: 6 mg/kg per day for 14 days) or saline (C) were s.c. implanted in lactating rats 2 days after giving birth (P2). At P120, N and C offspring were subdivided into four groups: 1) C - standard diet; 2) C with calcium supplementation (CCa, 10 g calcium carbonate/kg rat chow); 3) N - standard diet; and 4) N with calcium supplementation (NCa). Rats were killed at P180. As expected, N offspring showed higher visceral and total body fat, hyperleptinemia, lower hypothalamus leptin receptor (OB-R) content, hyperinsulinemia, and higher IR index. Also, higher tyrosine hydroxylase (TH) expression (+51%), catecholamine content (+37%), and serum 25-hydroxyvitamin D(3) (+76%) were observed in N offspring. Dietary calcium supplementation reversed adiposity, hyperleptinemia, OB-R underexpression, IR, TH overexpression, and vitamin D. However, this supplementation did not reverse hypothyroidism. In NCa offspring, Sirt1 mRNA was lower in visceral fat (-37%) and higher in liver (+42%). In conclusion, dietary calcium supplementation seems to revert most of the metabolic syndrome parameters observed in adult offspring programed by maternal nicotine exposure during lactation. It is conceivable that the reduction in fat mass per se, induced by calcium therapy, is the main mechanism that leads to the increment of insulin action.

Effects of a moderate physical training on the leptin synthesis by adipose tissue of adult rats submitted to a perinatal low-protein diet.

The aim of the study was to verify if moderate physical training affects leptin content in visceral and subcutaneous adipose tissue of adult rats subjected to a low-protein diet during the perinatal period. Male Wistar rats were divided into 2 groups according to their mothers diet during gestation and lactation: control (17% casein, C, n=12) and low-protein (8% casein, LP, n=12). On postnatal day 60, half of each group was submitted to moderate physical training (8 wks, 5 d · wk - 1, 60 min · d - 1, at 70% of VO2max, T) or not. After the physical training period, visceral and subcutaneous adipose tissues were removed. Leptin content was evaluated by western blotting. Starting from the fifth week on, T pups showed a reduction in the body weight. Similarly, LP+T offspring showed a lower body weight starting from the sixth week on. Western blotting analysis showed that leptin content in the visceral tissue was higher in the LP rats (p<0.01) and it was reversed in LP+T. No difference was found in the subcutaneous tissue. Moderate physical training attenuated the effects of a perinatal low-protein diet on the leptin content in visceral adipose tissue in adult offspring.

Developmental plasticity of endocrine disorders in obesity model primed by early weaning in dams.

Early weaning is associated with changes in the developmental plasticity. Here, we studied the adipocytes morphology, adipokines expression or content in adipose tissue as well as adrenal and thyroid function of neonate and adult offspring primed by early weaning. After birth, lactating rats were divided into 2 groups: EW (early weaning)--dams were wrapped with a bandage to block access to milk during the last 3 days of lactation, and Control--dams whose pups had free access to milk throughout lactation (21 days). At postnatal day (PN) 21, EW pups had lower visceral and subcutaneous adipocyte area (-67.7% and -62%, respectively), body fat mass (-26%), and leptin expression in visceral adipocyte (-64%) but higher leptin expression in subcutaneous adipocyte (2.9-fold increase). Adrenal evaluations were normal, but neonate EW pups presented lower serum T3 (-55%) and TSH (-44%). At PN 180, EW offspring showed higher food intake, higher body fat mass (+21.6%), visceral and subcutaneous adipocyte area (both 3-fold increase), higher leptin (+95%) and ADRβ3 (2-fold increase) content in visceral adipose tissue, and higher adiponectin expression in subcutaneous adipose tissue (+47%) but lower in visceral adipose tissue (-40%). Adult EW offspring presented higher adrenal catecholamine content (+31%), but no changes in serum corticosterone or thyroid status. Thus, early weaning primed for hypothyroidism at weaning, which can be associated with the adipocyte hypertrophy at adulthood. The marked changes in catecholamine adrenal content and visceral adipocyte ADRB3 are generally found in obesity, contributing to the development of other cardiovascular and metabolic disturbances.

Blocking leptin action one week after weaning reverts most of the programming caused by neonatal hyperleptinemia in the adult rat.

Hyperleptinemia during lactation programs for higher serum leptin in 30-day-old and adult rats, associated with metabolic changes. Here we evaluated the inhibition of serum leptin at 29 and 30 days on the metabolic phenotype of rats programmed with leptin during lactation. Pups from Wistar rats were saline-injected or leptin-injected from postnatal day 1 to day 10. At 29 and 30 days old, animals were injected with anti-leptin antibody (LA and CA) or saline (LS and CS). In adult animals, higher visceral (+53%) and total fat mass (+33%), hyperleptinemia (+67%), hypertriglyceridemia (+47%), and hypoadiponectinemia (-44%) observed in LS group compared to CS were prevented by immunoneutralization of leptin, since LA group had those parameters values similar to CS group. However, immunoblockade of leptin in normal animals led to the same metabolic changes seen in leptin-treated animals, in addition to lower serum adiponectin (-77% vs. CS) and higher insulin resistance index (+37%). Liver sirtuin1 (SIRT1) was higher (+41%) only in LA group, suggesting a role for SIRT1 in the prevention of leptin programming. Hypothalamic OBR was lower and SOCS3 higher in LS group and these changes were normalized in LA group. In conclusion, blocking leptin action one week after weaning seems to revert most of the alterations observed in rats programmed by neonatal hyperleptinemia. Higher liver SIRT1 expression may be one of the mechanisms involved, leading to a better glucose and lipid metabolism. Our data suggest that the lack or the excess of leptin programs an adverse metabolic phenotype in adulthood.

Prolactin inhibition at mid-lactation influences adiposity and thyroid function in adult rats.

Maternal hypoprolactinemia at the end of lactation (a precocious weaning model) increases milk leptin transfer and results in overweight, leptin resistance, and secondary hypothyroidism at adulthood. We studied the effects of prolactin (PRL) inhibition during mid-lactation (a partial malnutrition model) on milk leptin transfer, leptinemia, body composition, and thyroid function. Lactating rats were treated with bromocryptine (BRO, 1 mg/twice daily) or saline on days 7, 8, and 9 of lactation. Offspring were sacrificed 10, 21, and 90 days after birth. After treatment, BRO-treated dams showed hypoprolactinemia and hyperleptinemia, and produced less milk with lower levels of lactose and higher milk triglycerides. Milk leptin levels were lower at weaning. Offspring of BRO-treated dams had lower body weight and length as well as less visceral fat during lactation and adulthood. Total fat was also lower at weaning and adult life, whereas total protein was higher at 90 days-old. BRO offspring presented lower serum T4 and TSH at 10 days-old and weaning, respectively. When adults, these rats exhibited hypoleptinemia, lower levels of thyroid hormones, and higher TSH. Early inhibition of PRL therefore leads to offspring malnutrition and affects subsequent growth. Also, inhibition of PRL during lactation predisposes offspring to hypothyroidism; however, when the inhibition occurs during late lactation, the hypothyroidism is secondary, whereas when it is restricted to mid-lactation, the thyroid hypofunction is primary. The programming effect of milk suppression thus depends on the developmental stage of offspring.

Maternal prolactin inhibition causes changes in leptin at 22- and 30-day-old pups.

Breastfeeding is associated with obesity prevention. We showed previously that prolactin inhibition at the end of lactation causes hyperleptinemia at weaning (PN21) and programs for obesity, insulin resistance, dyslipidemia, and leptin resistance (PN180). Here, we evaluate the source of neonatal hyperleptinemia and how it develops during the nutritional transition from milk through solid food. Lactating rats were treated with bromocriptine (BRO), a prolactin inhibitor, 0.5 mg twice a day, or saline (CON) for the last 3 days of lactation. All parameters were studied at PN22 and PN30. At PN22, BRO-treated rats showed lower food intake, body mass, and body length. At PN30, only body length and mesenteric fat mass were lower. Despite normal plasma leptin levels at PN22, the adipose tissue leptin mRNA expression was lower, while plasma leptin was higher in PN30, possibly due to a higher adipose mesenteric tissue production. At PN22, the hypothalamus seems to be more sensitive to leptin, since OBR and STAT3 are higher. Conversely, at PN30 leptin signaling pathway is suggestive of leptin resistance with lower STAT3 and higher SOCS3 in hypothalamus and consequently higher NPY. Glycemia was lower at PN22 and higher at PN30, without changes in plasma insulin levels. At PN30, BRO-treated rats had other metabolic changes such as higher plasma cholesterol, lower HDL-c, higher hepatic cholesterol and AST, suggesting a liver dysfunction. Our data show that milk supply can exert a crucial role in the imprinting of a second leptin peak, which is important for survival adaptation to adverse nutritional conditions.

Ondansetron in the treatment of nausea and vomiting induced by chemotherapy

One-hundred and forty-five chemotherapy patients receiving cisplatin- and non-cisplatin-containing regimens participated in an open evaluation of ondansetron, a 5-HT3 receptor antagonist, in the prophylaxis of acute and delayed nausea and vomiting. The study had two groups of patients, one receiving cisplatin-containing regimens (Group A) and the other, non-cisplatin-containing regimens (Group B). There were 51 patients recruited to Group A. Ondansetron was given to these patients at a dose of 8 mg intravenously 15 min before chemotherapy, followed by an intravenous infusion for 24 h (1 mg/h), or 8 mg intravenously 4 and 8 h after the start of cisplatin, followed by 8 mg orally three times/day for 5 days. Ninety-four patients were recruited to Group B: these patients received ondansetron at a dose of 8 mg intravenously immediately before chemotherapy or 8 mg orally 1–2 h prior to it, and 8 mg orally three times/day for 3–5 days. For acute emesis (first 24 h), complete control was achieved in 79.5% of Group A patients and in 78.1% of Group B. For delayed emesis (days 2–5), 79.7% of Group A patients and 84.6% of Group B were completely protected during the entire study period. Nausea was also well controlled with ondansetron; 83.2% (Group A) and 86.5% (Group B) reported only mild nausea or no nausea at all. Ondansetron was effective in the control of both cisplatin- and non-cisplatin-induced emesis and well tolerated without any serious drug-related adverse events.

A semiquantitative approach to the impurity-band-related transport properties of GaMnAs nanolayers

We investigate the spin-polarized transport of GaMnAs nanolayers in which a ferromagnetic order exists below a certain transition temperature. Our calculation for the self-averaged resistivity takes into account the existence of an impurity band determining the extended (“metallic” transport) or localized (hopping by thermal excitation) nature of the states at and near the Fermi level. Magnetic order and resistivity are inter-related due to the influence of the spin polarization of the impurity band and the effect of the Zeeman splitting on the mobility edge. We obtain, for a given range of Mn concentration and carrier density, a “metallic” behavior in which the transport by extended carriers dominates at low temperature, and is dominated by the thermally excited localized carriers near and above the transition temperature. This gives rise to a conspicuous hump of the resistivity which has been experimentally observed and brings light onto the relationship between transport and magnetic properties of this material.